Does intermittent exposure to high altitude increase the risk of cardiovascular disease in workers? A systematic narrative review

Objective Several working groups (eg, miners, flight crews and soldiers) are subjected to chronic intermittent hypoxic exposure. The cardiovascular implications have been studied but not systematically reviewed with focus on possible negative health implications. The aim of the present review was to systematically evaluate the hypothesis that intermittent hypoxic exposure causes cardiovascular stress detrimental to health in workers. Design Systematic review. Data sources Electronic database search of PubMed, Scopus and Web of Science up to April 2020. Eligibility criteria Studies of workers ≥18 years repeatedly subjected to months to years of irregular intermittent hypoxia, lasting from a few hours (eg, flight crews), one or a few days (eg, soldiers), or several days to weeks (eg, miners working at high altitude), written in English and evaluating the effect of intermittent hypoxia on cardiovascular disease were included. Animal studies, books, book chapters, personal communication and abstracts were excluded. The primary outcome measure was changes in standardised mortality ratio. Data extraction and synthesis Two independent reviewers extracted data and assessed risk of bias using the Cochrane Collaboration’s tool. Results 119 articles were identified initially, 31 of which met the inclusion criteria. Of these, 17 were retrospective cohort mortality studies (irregular short-term intermittent hypoxia), and 14 studies were observational (long-term intermittent hypoxia). The population of irregular short-term intermittent hypoxia users (flight crew) showed a lower mortality by cardiovascular disease. Long-term intermittent hypoxia over several years such as in miners or soldiers may produce increased levels of cardiac disorders (12 studies), though this is probably confounded by factors such as obesity and socioeconomic status. Conclusion This systematic narrative review found that cardiovascular disease mortality in flight crews is lower than average, whereas miners and soldiers exposed to intermittent hypoxia experience increased risks of cardiovascular diseases. The impact of socioeconomic status and lifestyle appears of importance.Fundación Alfonso Martin Escudero' (Spain

Does Hypoxia and Stress Erythropoiesis Compromise Cardiac Function in Healthy Adults? A Randomized Trial

Objectives: To investigate whether recombinant human erythropoietin (rHuEPO) injections during an altitude training camp impact heart function. Methods: Thirty (12 women) moderately trained subjects stayed at 2320 m altitude for 4 weeks while training. Subjects were randomized to placebo (isotonic saline) or rHuEPO (20 IU/kg body weight) i.v. injections. Transthoracic echocardiography imaging was acquired 3 days after arrival to altitude and prior to the first placebo or rHuEPO injection as well as one day after the last rHuEPO injection three weeks later. Results: rHuEPO did not alter cardiovascular morphology parameters, systolic or diastolic function. In the placebo group, altitude exposure improved left ventricle (LV) systolic function due to an increased twist angle but rHuEPO had no additional effects. Pulmonary arterial systolic pressure was unaffected in either group. Notably, rHuEPO hampered LV untwist rate without affecting LV early filling. Conclusion: rHuEPO provided during mild altitude exposure does not cause any major effects on heart function. The observed alteration in LV untwist induced by rHuEPO is unlikely to have a meaningful clinical effect

Oxygen conserving mitochondrial adaptations in the skeletal muscles of breath hold divers

BackgroundThe performance of elite breath hold divers (BHD) includes static breath hold for more than 11 minutes, swimming as far as 300 m, or going below 250 m in depth, all on a single breath of air. Diving mammals are adapted to sustain oxidative metabolism in hypoxic conditions through several metabolic adaptations, including improved capacity for oxygen transport and mitochondrial oxidative phosphorylation in skeletal muscle. It was hypothesized that similar adaptations characterized human BHD. Hence, the purpose of this study was to examine the capacity for oxidative metabolism in skeletal muscle of BHD compared to matched controls.MethodsBiopsies were obtained from the lateral vastus of the femoral muscle from 8 Danish BHD and 8 non-diving controls (Judo athletes) matched for morphometry and whole body VO2max. High resolution respirometry was used to determine mitochondrial respiratory capacity and leak respiration with simultaneous measurement of mitochondrial H2O2 emission. Maximal citrate synthase (CS) and 3-hydroxyacyl CoA dehydrogenase (HAD) activity were measured in muscle tissue homogenates. Western Blotting was used to determine protein contents of respiratory complex I-V subunits and myoglobin in muscle tissue lysates.ResultsMuscle biopsies of BHD revealed lower mitochondrial leak respiration and electron transfer system (ETS) capacity and higher H2O2 emission during leak respiration than controls, with no differences in enzyme activities (CS and HAD) or protein content of mitochondrial complex subunits myoglobin, myosin heavy chain isoforms, markers of glucose metabolism and antioxidant enzymes.ConclusionWe demonstrated for the first time in humans, that the skeletal muscles of BHD are characterized by lower mitochondrial oxygen consumption both during low leak and high (ETS) respiration than matched controls. This supports previous observations of diving mammals demonstrating a lower aerobic mitochondrial capacity of the skeletal muscles as an oxygen conserving adaptation during prolonged dives.</div

The Erythropoietin Receptor Stimulates Rapid Cycling and Formation of Larger Red Cells During Mouse and Human Erythropoiesis [preprint]

Erythroid terminal differentiation entails cell divisions that are coupled to progressive decreases in cell size. EpoR signaling is essential for the survival of erythroid precursors, but it is unclear whether it has other functions in these cells. Here we endowed mouse precursors that lack the EpoR with survival signaling, finding that this was sufficient to support their differentiation into enucleated red cells, but that the process was abnormal. Precursors underwent fewer and slower cell cycles and yet differentiated into smaller red cells. Surprisingly, EpoR further accelerated cycling of early erythroblasts, the fastest cycling cells in the bone marrow, while simultaneously increasing their cell size. EpoR-mediated formation of larger red cells was independent of the established pathway regulating red cell size by iron through Heme-regulated eIF2α kinase (HRI). We confirmed the effect of Epo on red cell size in human volunteers, whose mean corpuscular volume (MCV) increased following Epo administration. This increase persisted after Epo declined and was not the result of increased reticulocytes. Our work reveals a unique effect of EpoR signaling on the interaction between the cell cycle and cell growth. Further, it suggests new diagnostic interpretations for increased red cell volume, as reflecting high Epo and erythropoietic stress